Performance goals for the laboratory testing of antithrombin, protein C and protein S

Summary

To achieve a reliable analytical quality for both monitoring and diagnostic testing, laboratories need to fulfil the widely accepted analytical performance goals based on the biological variation of the analytes of testing. Not only is the short-term analytical performance, which regularly is assessed by internal quality control procedures, of importance, but also the long-term analytical performance. To assess the long-term analytical performance, data obtained from an external quality assessment programme can be used. In this study we have used the evaluation model designed by the ECAT Foundation for the assessment of the longterm analytical performance, including imprecision, bias and total analytical error. The model was applied to the data from 136 different laboratories for the assay of antithrombin (activity), protein C (activity and antigen) and protein S (activity, total and free antigen). The imprecision (median; range), reflected by the long-term analytical coefficient of variation (LCV_A), was the lowest for antithrombin (7.6%; 2.6 – 43.8%) and the highest for protein S activity (17.2%; 4.3 – 88.6%). For bias and total error the same pattern was observed (antithrombin: 3.8%; 0.3 – 17.1% and 9.1%; 3.4 – 34.3%, respectively; protein S activity: 12.8%; 3.1 – 34.8% and 24.5%; 9.9 – 87.0%, respectively). For the majority of the laboratories (70 – 85%) the imprecision contributes considerably more to the total error than the bias. However the effect of the bias on the analytical quality is not negligible. Assays for antithrombin, protein C and protein S are mainly used for diagnostic testing. About 70 – 100% of the laboratories can fulfil the desirable performance goal for imprecision. The desirable performance goal for bias was reached by 50 – 95% of the laboratories. In all cases the highest numbers of laboratories fulfilling performance goals was obtained for the protein C variables. To improve the analytical quality in assays of antithrombin, protein C and protein S it is highly recommended that primarily imprecision (non-systematic failures) be suppressed. However the effect of the bias (systematic failures) on the analytical quality should not be neglected. A useful tool for determining the imprecision (LCV_A) and bias is the long-term analytical performance evaluation model as used by the ECAT Foundation.

Keywords

Thrombophilia - analytical performance - long-term - EQA

• References

• 1 Lane DA, Mannucci PM, Bauer K, Bertina RM, Bochkov NP, Boulyjenkov V. et al. Inherited Thrombophilia: Part I. Thromb Haemost 1996; 76: 651-62.
• 2 Lane DA, Mannucci PM, Bauer K. et al. Inherited Thrombophilia: Part II. Thromb Haemost 1996; 76: 824-34.
• 3 Michiels JJ, Hamulyák K. Laboratory diagnosis of hereditary thrombophilia. Sem Thromb Haemostas 1998; 24: 309-19.
• 4 De Moerloose Ph, Bounameaux HR, Mannucci PM. Screening tests for thrombophilic patients: which tests, for which patient, by whom, when and why?. Sem Thromb Haemostas 1998; 24: 321-7.
• 5 Walker ID, Greaves M, Preston FE. Investigation and management of heritable thrombophilia. BrJ Haematol 2001; 114: 512-28.
• 6 Libeer JC, Baadenhuijsen H, Fraser GC. et al. Characterisation and classification of external quality assessment schemes (EQA) according to objectives such as evaluation of method and participant bias and standard deviation. Eur J Clin Chem Clin Biochem 1996; 34: 665-78.
• 7 Hyltoft PPetersen, Ricós C, Stöckl D. et al. Proposed guidelines for internal quality control of analytical results in the medical laboratory. Eur J Clin Chem Clin Biochem 1996; 34: 983-99.
• 8 Groth T, De Verdier CH. Transferability of clinical laboratory data. UpsalaJ Med Sci 1993; 98: 259-74.
• 9 Büttner J. Reference materials and reference methods in laboratory medicine: a challenge to international co-operation. Eur J Clin Chem Clin Biochem 1994; 32: 571-7.
• 10 Ehrmeyer SS, Laessig RH. Alternative statistical approach to evaluating interlaboratory performance. Clin Chem 1985; 31: 106-8.
• 11 Fraser CG, Hyltoft PPetersen. Desirable standards for laboratory tests if they are to fulfil medical needs. Clin Chem 1993; 39: 1447-55.
• 12 Doumas BT. The evaluation and limitations of accuracy and precision standards. Clin Chim Acta 1997; 260: 145-62.
• 13 Meijer P, De Maat MPM, Kluft C. et al. Assessment of the long-term analytical performance of field methods in haemostasis by evaluation of results of an external quality assessment programme. Clin Chem 2002; 48: 1011-5.
• 14 Meijer P, Kluft C, Haverkate F. et al. The long-term with in and between-laboratory variability for assay of antihrombin, and proteins C and S: results derived from the external quality assessment program for thrombophilia screening of the ECAT Foundation. J Thromb Haemost 2003; 01: 748-53.
• 15 Stöckl D, Baadenhuijsen H, Fraser CG. et al. Desirable routine analytical goals for quantities assayed in serum. Eur J Clin Chem Clin Biochem 1995; 33: 157-69.
• 16 Fraser CG. General strategies to set quality specifications for reliability performance characteristics. Scand J Clin Lab Invest 1999; 59: 487-90.
• 17 Cotlove E, Harris EK, Williams GZ. Components of variation in long-term studies of serum constituents in normal subjects. III. Physiological and medical implications. Clin Chem 1970; 16: 1028-32.
• 18 Harris EK. Statistical principles underlying analytical goal-setting in clinical chemistry. Am J Clin Pathol 1979; 72: 364-82.
• 19 Gowans EMS, Hyltoft PPetersen, Blaabjerg O. et al. Analytical goals for the acceptance of common reference intervals for laboratories throughout a geographical area. Scand J Clin Lab Invest 1988; 48: 757-64.
• 20 Fraser CG, Hyltoft PPetersen, Lytken MLarsen. Setting analytical goals for random analytical error in specific clinical monitoring situations. Clin Chem 1990; 36: 1625-8.
• 21 Fuentes-Arderiu X, Fraser CG. Analytical goals for interference. Ann Clin Biochem 1991; 28: 393-5.
• 22 Fraser CG, Hyltoft PPetersen, Ricos C. et al. Proposed quality specifications for the imprecision and inaccuracy of analytical systems for clinical chemistry. Eur J Clin Chem Clin Biochem 1992; 30: 311-7.
• 23 Klee GG. Tolerance limits for short-term analytical bias and analytical imprecision derived from clinical assay specificity. Clin Chem 1993; 39: 1514-8.
• 24 Fraser CG, Hyltoft PPetersen, Libeer JC. et al. Proposals for setting generally applicable quality goals solely based on biology. Ann Clin Biochem 1997; 34: 8-12.
• 25 Mina A. A new quality control model using performance goals based on biological variation in external quality assurance schemes. Clin Chem Lab Med 2006; 44: 86-91.
• 26 Costongs GMPJ, Bas BM, Janson PCW. Short-term and long-term intra-individual variations and critical differences of coagulation parameters. J Clin Chem Clin Biochem 1985; 23: 405-10.
• 27 Thompson SG, Martin JC, Meade TW. Sources of variability in coagulation factor assays. Thromb Haemost 1987; 58: 1073-7.
• 28 Chambless LE, McMahon R, Wu KK. et al. Shortterm intra-individual variability in hemostasis factors. The ARIC study. Ann Epidemiol 1992; 02: 723-33.
• 29 Nguyen ND, Ghaddar H, Stinson V. et al. ARIC Hemostasis Study-IV. Intra-individual variability and reliability of hemostatic factors. Thromb Haemost 1995; 73: 256-60.
• 30 Marckmann P, Sandström B, Jespersen J. The variability of and associations between measures of blood coagulation, fibrinolysis and blood lipids. Atherosclerosis 1992; 96: 235-44.
• 31 Blombäck M, Eneroth P, Landgren BM. et al. On the intraindividual and gender variability of haemostatic components. Thromb Haemost 1992; 67: 70-5.
• 32 Dot D, Miró J, Fuentes-Arderiu X. Within-subject and between-subject biological variation of prothrombin time and activated partial thromboplastin time. Ann Clin Biochem 1992; 29: 422-5.
• 33 De Maat MPM, de Bart ACW, Hennis BC. et al. Interindividual and intraindividual variability in plasma fibirnogen, tPA antigen, PAI activity, and CRP in healthy, young volunteers and patients with angina pectoris. Atheros Thromb Vasc Biol 1996; 16: 1156-62.
• 34 Salomaa V, Rasi V, Stengård J. et al. Intra- and interindividual variability of hemostatic factors and traditional cardiovascular risk factors in a three-year followup. Thromb Haemost 1998; 79: 969-74.
• 35 Riese H, Vrijkotte TGM, Meijer P. et al. Covariance of metabolic and haemostatic risk indicators in men and women. Fibrinol Proteol 2001; 14: 1-12.
• 36 Ricós C, Alvarez V, Cava F. et al. Current database on biological variation: pros, cons and progress. Scand J Clin Lab Invest 1999; 59: 491-500.
• 37 Database on biological variation at Westgard website. Available at http://www.westgard.com/biodatabase1.htm
• 38 Thompson SG, Duckert F, Haverkate F. The measurement of haemostatic factors in 16 European laboratories. Quality assessment for the multicentre ECAT Angina Pectoris Study. Thromb Haemost 1989; 61: 301-6.
• 39 Haverkate F, Walker ID, Conkie J. External quality assessment of thrombophilia testing in Europe. Fibrinolysis 1996; 10 (Suppl. 02) 169.
• 40 Meijer P, Haverkate F. External quality assessment and the laboratory diagnosis of thrombophilia. Semin Thromb Hemost 2005; 31: 59-65.
• 41 Kirkwood TBL, Barrowcliffe TW, Thomas DP. An international collaborative study establishing a reference preparation for antithrombin III. Thromb Haemost 1980; 43: 10-5.
• 42 Hubbard AR. Standardization of protein C in plasma: establishment of an international standard. Thromb Haemost 1988; 59: 464-67.
• 43 Hubbard AR. Standardization of protein S in plasma: calibration of the 1st international standard. Thromb Haemost 1997; 78: 1237-41.
• 44 Bertina RM. Protein S antigen. In: Laboratory Techniques in Thrombosis. A manual, 2nd revised edition of ECAT Assay Procedures. Dordrecht: Kluwer Academic Publishers; 1999: 141-51.